EP0023706A1 - 4-Phenoxy piperidines, process for their preparation, their use and medicaments containing them - Google Patents

Abstract

4-Phenoxypiperidines of the general formula I <IMAGE> (I) wherein R1 denotes a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, R2 denotes a hydrogen atom, a nitro group, an amino group or an acylamino group and R3 denotes a phenyl group or a benzyl group, and their N-oxides and their acid-addition salts are new compounds. They have an antiptotic and analgesic action and are suitable for the treatment of depressions and painful conditions. Processes for the preparation of the new compounds are provided.

Description

The compounds according to the invention are used in the pharmaceutical industry as intermediates and for the manufacture of medicaments.

German Offenlegungsschrift DE 27 35 051 describes 4-phenylpiperidines which have an antidepressant, antiagressive, diuretic, antiparkinsonian, bronchodilatory and antiarthritic activity. Significance with regard to the pharmacological activity of these compounds is attributed to a hydroxyl group in the 3-position of the piperidine ring or an ester derivative thereof, esterified hydroxyl groups in the 3-position and 4-position of the piperidine ring are said to be particularly important. In contrast, certain 4-phenoxypiperidines which are unsubstituted in the 3-position now have pharmacologically interesting and specific properties.

worin

• R¹ ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 5 Kohlenstoffatomen, eine Alkenylgruppe mit 3 bis 5 Kohlenstoffatomen, eine Cycloalkylmethylgruppe mit 3 bis 7 Kohlenstoffatomen im Cycloalkylteil oder eine Phenylalkylgruppe mit 1 bis 3 Kohlenstoffatomen im Alkylteil,
• R² ein Wasserstoffatom, eineNitrogruppe, eine Aminogruppe oder eine Acylaminogruppe und
• _R ³ eine Phenylgruppe oder eine Benzylgruppe bedeuten, sowie ihre N-Oxide und ihre Säureadditionssalze.

The invention relates to 4-phenoxypiperidines of the general formula I.

wherein

• R ^{1 is} a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part,
• R ^{2 represents} a hydrogen atom, a nitro group, an amino group or an acylamino group and
• _R ^{3 represents} a phenyl group or a benzyl group, as well as their N-oxides and their acid addition salts.

Alkyl groups and alkenyl groups can be straight-chain or branched. For example, the alkyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl and tert-pentyl group and the alkenyl group the allyl and 2 -Methylallylgruppe called. The methyl, tert-butyl and allyl groups are preferred.

Examples of cycloalkylmethyl groups include the cyclobutylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl and cyclopropylmethyl groups. The cyclopropylmethyl group is preferred.

Phenylalkyl groups are, for example, the benzyl, 1-phenylethyl, 2-phenylethyl and 3-phenylpropyl group, the benzyl group being preferred.

As acyl residues from the acylamino groups, the customary acyl groups used to protect amino groups come into consideration. Examples include alkylcarbonyl groups with 1 to 5 carbon atoms in the alkyl part and alkoxycarbonyl groups with 1 or 2 carbon atoms in the alkoxy part and a benzoyl group which is optionally substituted by chlorine, bromine, fluorine, methyl, trifluoromethyl or methoxy substituents.

All acid addition salts are suitable as salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts are converted into pharmacologically acceptable salts by processes known to those skilled in the art. Examples include water-soluble or water-insoluble acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate [2- (4-hydroxybenzoyl) benzoate], fendizoate (2- [ (2'-hydroxy-4-biphenylyl) carbonyl] benzoate), propionate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4,4'-diaminostilbene-2,2 ' disulfonate), embonate [4,4'-methylene-bis (3-hydroxy-2-naphthoate)], metembonate [4,4'-methylene-bis- (3-methoxy-2-naphthoate)], stearate, Tosilate (p-toluenesulfonate), 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, mesilate (methanesulfonate).

worin

• R^1* ein Wasserstoffatom, eine geradkettige Alkylgruppe mit 1 bis 3 Kohlenstoffatomen oder eine Phenylalkylgruppe mit 1 oder 2 Kohlenstoffatomen im Alkylteil,
• R^2* ein Wasserstoffatom, eine Nitrogruppe, eine Aminogruppe oder eine Alkylcarbonylaminogruppe mit 1 bis 5 Kohlenstoffatomen und
• R^3* eine Phenylgruppe oder eine Benzylgruppe bedeuten,

sowie ihre N-Oxide und ihre Säureadditionssalze.One embodiment of the invention is 4-phenoxypiperidines of the general formula I ^*

wherein

• R ^{1 * represents} a hydrogen atom, a straight-chain alkyl group with 1 to 3 carbon atoms or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part,
• R ^{2 * represents} a hydrogen atom, a nitro group, an amino group or an alkylcarbonylamino group with 1 to 5 carbon atoms and
• R ^{3 * represents} a phenyl group or a benzyl group,

as well as their N-oxides and their acid addition salts.

Preferred representatives of embodiment I ^* are those in which R1 * denotes a hydrogen atom, a methyl group or a benzyl group, R ^{2 *} denotes a hydrogen atom, a nitro group or an amino group and R ^{3 *} denotes a phenyl group or a benzyl group, and their N-oxides and their acid addition salts.

Particularly preferred representatives of embodiment I ^* are those in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * is} a hydrogen atom, a nitro group or an amino group and R ^{3 * is} a phenyl group, and their pharmacologically acceptable acid addition salts.

Selected representatives of embodiment I ^* are those in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * is} an amino group and R ^{3 * is} a phenyl group, and also their pharmacologically acceptable acid addition salts.

worin

• R^1** eine verzweigtkettige Alkylgruppe mit 3 bis 5 Kohlenstoffatomen, eine Alkenylgruppe mit 3 bis 5 Kohlenstoffatomen oder eine Cycloalkylmethylgruppe mit 3 bis 5 Kohlenstoffatomen im Cycloalkylteil,
• R ^2** ein Wasserstoffatom, eine Nitrogruppe, eine Aminogruppe oder eine Alkylcarbonylaminogruppe mit 1 bis 5 Kohlenstofatomen und
• R^3** eine Phenylgruppe oder eine Benzylgruppe bedeuten,

sowie ihre N-Oxide und ihre Säureadditionssalze.Another embodiment of the invention are 4-phenoxypiperidines of the general formula I ^**

wherein

• R ^{1 ** is} a branched-chain alkyl group with 3 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms or a cycloalkylmethyl group with 3 to 5 carbon atoms in the cycloalkyl part,
• R ^{2 ** represents} a hydrogen atom, a nitro group, an amino group or an alkylcarbonylamino group with 1 to 5 carbon atoms and
• R ^{3 ** represents} a phenyl group or a benzyl group,

as well as their N-oxides and their acid addition salts.

Preferred representatives of embodiment I ^** are those in which R ^{1 ** is} a branched-chain alkyl group having 3 to 5 carbon atoms, an allyl group or a cyclopropylmethyl group, R ^{2 ** is} a hydrogen atom, a nitro group or an amino group and R ^{3 ** is} a phenyl group or a benzyl group, as well as their N-oxides and their acid addition salts.

Particularly preferred representatives of embodiment I ^** are those in which R ^{1 ** is} an isopropyl group or tert-butyl group, R ^{2 ** is} a hydrogen atom, a nitro group or an amino group and R ^{3 ** is} a phenyl group, and their pharmacologically acceptable Acid addition salts.

• 1-Ethyl-4-phenoxy-4-phenylpiperidin,
• 1-Cyclobutylmethyl-4-phenoxy-4-phenylpiperidin,
• 1-Isobutyl-4-phenoxy-4-phenylpiperidin,
• 1-(3-Phenylpropyl)-4-phenoxy-4-phenylpiperidin,
• 1-Neopentyl-4-phenoxy-4-phenylpiperidin,
• 1-Benzyl-4-phenoxy-4-phenylpiperidin,
• 1-Isopropyl-4-phenoxy-4-phenylpiperidin-N-oxid,
• 1-n-Butyl-4-benzyl-4-phenoxypiperidin,
• 4-Benzyl-1-ethyl-4-phenoxypiperidin,
• 4-Benzyl-1-cyclohexylmethyl-4-phenoxypiperidin,
• 4-Benzyl-1-propyl-4-phenoxypiperidin,
• 4-Benzyl-1-sek.-butyl-4-phenoxypiperidin,
• 4-Benzyl-1-isopentyl-4-phenoxypiperidin,
• 4-Benzyl-1-methyl-4-phenoxypiperidin-N-oxid,
• 1-Benzyl-4-(4-nitrophenoxy)-4-phenylpiperidin,
• 1-Cyclopentylmethyl-4-(4-nitrophenoxy)-4-phenylpiperidin,
• 1-Ethyl-4-(4-nitrophenoxy)-4-phenylpiperidin,
• 1-n-Butyl-4-(4-nitrophenoxy)-4-phenylpiperidin,
• 1-tert.-Butyl-4-(4-nitrophenoxy)-4-phenylpiperidin-N-oxid,
• 1-Neopentyl-4-(4-nitrophenoxy)-4-phenylpiperidin,
• 4-(4-Nitrophenoxy)-4-phenyl-1-(3-phenylpropyl)-piperidin,
• 1,4-Dibenzyl-4-phenoxypiperidin,
• 4-Benzyl-1-ethyl-4-phenoxypiperidin-N-oxid,
• 4-Benzyl-1-cyclopropylmethyl-4-phenoxypiperidin,
• 4-Benzyl-1-isobutyl-4-phenoxypiperidin,
• 4-Benzyl-1-isopentyl-4-phenoxypiperidin-N-oxid,
• 4-Benzyl-1-neopentyl-4-phenoxypiperidin,
• 4-Benzyl-1-n-butyl-4-phenoxypiperidin-N-oxid,
• 4-Benzyl-4-phenoxypiperidin,
• 4-(4-Aminophenoxy)-1-ethyl-4-phenylpiperidin,
• 4-(4-Aminophenoxy)-1-cyclopropylmethyl-4-phenylpiperidin,
• 4-(4-Aminophenoxy)-1-neopentyl-4-phenylpiperidin,
• 4-(4-Aminophenoxy)-4-phenyl-1-(3-phenylpropyl)-piperidin,
• 4-(4-Aminophenoxy)-1-n-butyl-4-phenylpiperidin,
• 1-Ethyl-4-(4-isobutyrylaminophenoxy)-4-phenylpiperidin,
• 1-Isopropyl-4-phenyl-4-(4-propionylaminophenoxy)piperidin,
• 1-n-Butyl-4-{4-n-hexanoylaminophenoxy)-4-phenylpiperidin,
• 4-Benzyl-1-ethyl-4-(4-isöbutyrylaminophenoxy)piperidin,
• 4-Benzyl-1-isopropyl-4-(4-n-pentanoylaminophenoxy)piperidin,
• 4-Benzyl-1-ethyl-4-(4-propionylaminophenoxy)piperidin
• und ihre Säureadditionssalze.

Representatives of the compounds of the invention may be mentioned, for example

• 1-ethyl-4-phenoxy-4-phenylpiperidine,
• 1-cyclobutylmethyl-4-phenoxy-4-phenylpiperidine,
• 1-isobutyl-4-phenoxy-4-phenylpiperidine,
• 1- (3-phenylpropyl) -4-phenoxy-4-phenylpiperidine,
• 1-neopentyl-4-phenoxy-4-phenylpiperidine,
• 1-benzyl-4-phenoxy-4-phenylpiperidine,
• 1-isopropyl-4-phenoxy-4-phenylpiperidine-N-oxide,
• 1-n-butyl-4-benzyl-4-phenoxypiperidine,
• 4-benzyl-1-ethyl-4-phenoxypiperidine,
• 4-benzyl-1-cyclohexylmethyl-4-phenoxypiperidine,
• 4-benzyl-1-propyl-4-phenoxypiperidine,
• 4-benzyl-1-sec-butyl-4-phenoxypiperidine,
• 4-benzyl-1-isopentyl-4-phenoxypiperidine,
• 4-benzyl-1-methyl-4-phenoxypiperidine-N-oxide,
• 1-benzyl-4- (4-nitrophenoxy) -4-phenylpiperidine,
• 1-cyclopentylmethyl-4- (4-nitrophenoxy) -4-phenylpiperidine,
• 1-ethyl-4- (4-nitrophenoxy) -4-phenylpiperidine,
• 1-n-butyl-4- (4-nitrophenoxy) -4-phenylpiperidine,
• 1-tert-butyl-4- (4-nitrophenoxy) -4-phenylpiperidine-N-oxide,
• 1-neopentyl-4- (4-nitrophenoxy) -4-phenylpiperidine,
• 4- (4-nitrophenoxy) -4-phenyl-1- (3-phenylpropyl) piperidine,
• 1,4-dibenzyl-4-phenoxypiperidine,
• 4-benzyl-1-ethyl-4-phenoxypiperidine N-oxide,
• 4-benzyl-1-cyclopropylmethyl-4-phenoxypiperidine,
• 4-benzyl-1-isobutyl-4-phenoxypiperidine,
• 4-benzyl-1-isopentyl-4-phenoxypiperidine-N-oxide,
• 4-benzyl-1-neopentyl-4-phenoxypiperidine,
• 4-benzyl-1-n-butyl-4-phenoxypiperidine-N-oxide,
• 4-benzyl-4-phenoxypiperidine,
• 4- (4-aminophenoxy) -1-ethyl-4-phenylpiperidine,
• 4- (4-aminophenoxy) -1-cyclopropylmethyl-4-phenylpiperidine,
• 4- (4-aminophenoxy) -1-neopentyl-4-phenylpiperidine,
• 4- (4-aminophenoxy) -4-phenyl-1- (3-phenylpropyl) piperidine,
• 4- (4-aminophenoxy) -1-n-butyl-4-phenylpiperidine,
• 1-ethyl-4- (4-isobutyrylaminophenoxy) -4-phenylpiperidine,
• 1-isopropyl-4-phenyl-4- (4-propionylaminophenoxy) piperidine,
• 1-n-butyl-4- {4-n-hexanoylaminophenoxy) -4-phenylpiperidine,
• 4-benzyl-1-ethyl-4- (4-isobutyrylaminophenoxy) piperidine,
• 4-benzyl-1-isopropyl-4- (4-n-pentanoylaminophenoxy) piperidine,
• 4-benzyl-1-ethyl-4- (4-propionylaminophenoxy) piperidine
• and their acid addition salts.

• 1-Methyl-4-phenoxy-4-phenylpiperidin,
• 4-(4-Aminophenoxy)-4-benzyl-1-methylpiperidin,
• 4-(4-Acetaminophenoxy)-1-methyl-4-phenylpiperidin, insbesondere
• 4-(4-Aminophenoxy)-1-methyl-4-phenylpiperidin
• und ihre pharmakologisch verträglichen Säureadditionssalze.

Selected compounds available according to the invention are

• 1-methyl-4-phenoxy-4-phenylpiperidine,
• 4- (4-aminophenoxy) -4-benzyl-1-methylpiperidine,
• 4- (4-acetaminophenoxy) -1-methyl-4-phenylpiperidine, in particular
• 4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine
• and their pharmacologically acceptable acid addition salts.

The 4-phenoxypiperidines of the general formula I or of the embodiments I ^* and I ^** , their N-oxides and their acid addition salts have valuable properties which make them commercially usable. On the one hand, the compounds, their N-oxides and their pharmacologically, ie biologically compatible, acid addition salts have a pronounced antiptotic activity which is coupled with a strong analgesic effect. On the other hand, the compounds are intermediates for the preparation of pharmacologically active 4-phenoxypiperidines.

For example, compounds of the general formula I in which R ¹ denotes a phenylalkyl group, in particular a benzyl group, can be converted into compounds of the formula I by splitting off the phenylalkyl group in which R ^{1 represents} a hydrogen atom. These compounds serve as valuable starting compounds for the preparation of derivatives of the general formula I in which R ^{1 represents} an alkyl, alkenyl or cycloalkylmethyl group. 4-phenoxypiperidines of the general formula I, in which R ² denotes a nitro group, are intermediates for the preparation of those compounds of the general formula I in which R ² denotes an amino or acylamino group or a hydrogen atom.

The antiptotic effect of the compounds according to the invention is expressed in a strong reserpine antagonism at a low dose. The pronounced analgesic effect can be demonstrated in various analgesia animal models, this effect being antagonizable by naloxone. The central stimulating effect of the compounds according to the invention is not antagonized by naloxone, rather enhanced, so that different action centers in mammals must be concluded for the two effects.

The excellent pharmacological activity of the compounds according to the invention enables them to be used in human medicine as antidepressants and analgesics, they being used for prophylaxis and above all for the treatment of symptoms that have already occurred.

As indications for the human medical field, depression of various athliology and symptomatology, such as endogenous depression, psychogenic depression, exhaustion depression, depressive moods, may be mentioned for men or women of all ages, for example; and pain states of various origins, in particular chronic pain states that lead to or are associated with depression.

The invention therefore furthermore relates to a process for the treatment of mammals which are suffering from one of the abovementioned diseases. The method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more compounds of the general formulas I, I ^* , I ^** , their preferred representatives and / or their acid addition salts and / or N-oxides.

The invention also relates to the use of compounds according to the invention in combating the diseases mentioned above. The invention also encompasses the use of compounds according to the invention in the production of medicaments which are used to combat the diseases mentioned.

worin

• R¹ ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 5 Kohlenstoffatomen, eine Alkenylgruppe mit 3 bis 5 Kohlenstoffatomen, eine Cycloalkylmethylgruppe mit 3 bis 7 Kohlenstoffatomen im Cycloalkylteil oder eine Phenylalkylgruppe mit 1 bis Kohlenstoffatomen im Alkylteil,
• R ein Wasserstoffatom, eine Nitrogruppe, eine Aminogruppe oder eine Acylaminogruppe und
• R³ eine Phenylgruppe oder eine Benzylgruppe bedeuten,

und/oder ihre pharmakologisch verträglichen N-Oxide und/oder Säureadditionssalze enthalten.The invention further relates to medicaments which contain one or more 4-phenoxypiperidines of the general formula I.

wherein

• R ^{1 represents} a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to carbon atoms in the alkyl part,
• R is a hydrogen atom, a nitro group, an amino group or an acylamino group and
• R ^{3 represents} a phenyl group or a benzyl group,

and / or contain their pharmacologically acceptable N-oxides and / or acid addition salts.

Refinements of the medicaments are those which contain pharmacologically active and tolerable 4-phenoxypiperidines of the general formula I ^* or I ^** or their preferred representatives, their N-oxides and / or their acid addition salts.

The compounds according to the invention are formulated into medicaments by methods known per se. The new compounds can be used as medicaments as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of these mixtures is 5 to 95, preferably 25 to 75 percent by weight of the total mixture.

In accordance with the invention, the active ingredients can be used in any form, for example systemically, in the human-medical field, provided that the formation or maintenance of from sufficient blood or tissue levels of active ingredient is guaranteed. This can be achieved either by oral, rectal or parenteral administration in suitable doses. The pharmaceutical preparation of the active ingredient is advantageously in the form of unit doses which are tailored to the desired administration. A unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion, a suspension, a sol or a gel.

“Unit dose” in the sense of the present invention is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or multiple of a single therapeutic dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score line.

The pharmaceutical preparations according to the invention contain when they are in unit doses and for application e.g. are intended for humans, about 0.5 to 50 mg, advantageously 5 to 40 mg and in particular 10 to 30 mg of active ingredient.

In general, it has proven to be advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 1.0 to about 50, preferably 5 to 50, in particular 10 to 30 mg, optionally in the form of several, preferably 1 to 3 individual doses to achieve the desired results. A single dose contains the active ingredient (s) in amounts of about 0.5 to about 25, preferably 3 to 15, in particular 5 to 10 mg.

In the case of long-term medication, the therapeutic administration of the pharmaceutical preparation is generally carried out at fixed times, such as 1 to 3 times a day, e.g. after meals and / or in the evening. On acute occasions, medication takes place at different times. Under certain circumstances, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the patient to be treated, the type and severity of the disease, the type of preparation and the application of the drug, and the period or interval within which the administration takes place. In the case of creeping therapy, it is appropriate to start with less than the above-mentioned amount of active ingredient and to only reach the above-mentioned amount of active ingredient in the course of the treatment. The person skilled in the art can determine the optimum dosage and type of application of the active ingredients required at any time on the basis of his specialist knowledge.

The pharmaceutical preparations generally consist of the active compounds according to the invention and non-toxic, pharmaceutically acceptable pharmaceutical carriers which are used as admixtures or diluents in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a bag or another container, for the therapeutically active ingredient. A carrier can e.g. serve as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.

For oral use, e.g. Tablets, dragees, hard and soft capsules ,. e.g. made of gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.

Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, for example corn starch or alginates; Binders, for example starch, gelatin or acacia; and lubricants, for example aluminum or magnesium stearate, talc or silicone oil. You can also add a cover be provided, which can also be such that it achieves a delayed dissolution and absorption of the drug in the gastrointestinal tract and thus, for example, better tolerance, protracting or retardation. Gelatin capsules can contain the drug mixed with a solid, for example calcium carbonate or kaolin, or an oily, for example olive, peanut or paraffin oil, diluent.

Aqueous suspensions can include suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth or acacia; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.

oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.

Water-dispersible powders and granules, the drugs can be mixed with dispersing, wetting and suspending agents, e.g. the above, as well as with sweeteners, flavoring agents and colorants.

Emulsions can e.g. Olive, peanut or paraffin oil in addition to emulsifiers, e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.

Suppositories are used for rectal use of the medicinal products, which are produced with the help of binders melting at rectal temperature, for example cocoa butter or polyethylene glycols.

Sterile injectable aqueous solutions, e.g. isotonic salt solutions, or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents; e.g. Propylene or butylene glycol.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.

In addition to the 4-phenoxypiperidines according to the invention, their pharmacologically acceptable N-oxides or their acid addition salts, the pharmaceutical preparations can additionally contain one or more pharmacologically active constituents from other pharmaceutical groups, for example mild stimulants, such as caffeine; Analgesics such as aminophenazone, acetylsalicylic acid; Antiphlogistics, such as phenylbutazone, indomethacin, (hetero) arylacetic acids; Minor tranquilizers, such as meprobamate, chlordiazepoxide, diazepam; Major tranquilizers, such as perazine, fluophenazine, cerebral circulation-promoting and cerebral metabolism-promoting agents and / or roborants, such as glutamic acid, inorganic salts, vitamins or combinations thereof.

worin

• R ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 5 Kohlenstoffatomen, eine Alkenylgruppe mit 3 bis 5 Kohlenstoffatomen, eine Cycloalkylmethylgruppe mit 3 bis 7 Kohlenstoffatomen im Cycloalkylteil oder eine Phenylalkylgruppe mit 1 bis 3 Kohlenstoffatomen im Alkylteil,
• R ein Wasserstoffatom, eine Nitrogruppe, eine Aminogruppe oder eine Acylaminogruppe und
• R³ eine Phenylgruppe oder eine Benzylgruppe bedeuten,

The process according to the invention for the preparation of the 4-phenoxypiperidines of the more general formula I

wherein

• R is a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part,
• R is a hydrogen atom, a nitro group, an amino group or an acylamino group and
• R ^{3 represents} a phenyl group or a benzyl group,

worin R die oben angegebene Bedeutung hat und

• R⁴ eine Alkylgruppe mit 1 bis 5 Kohlenstoffatomen, eine Alkenylgruppe mit 3 bis 5 Kohlenstoffatomen, eine Cycloalkylmethylgruppe mit 3 bis 7 Kohlenstoffatomen im Cycloalkylteil, eine Phenylalkylgruppe mit 1 bis 3 Kohlenstoffatomen im Alkylteil oder eine R^5-CO-Gruppe und
• R⁵ ein Wasserstoffatom, eine Alkylgruppe mit 1. bis 4 Kohlenstoffatomen, eine Alkenylgruppe mit 2 bis 4 Kohlenstoffatomen, eine Cycloalkylgruppe mit 3 bis 7 Kohlenstoffatomen, eine Phenylgruppe oder eine Phenylalkylgruppe mit 1 oder 2 Kohlenstoffatomen im Alkylteil bedeuten, oder ein Salz davon mit 4-Nitrofluorbenzol in einem aprotischen Lösungsmittel in Gegenwart einer starken Base umsetzt und gegebenenfalls anschließend das erhaltene Reaktionsprodukt einem oder mehreren der folgenden Verfahrensschritte unterwirft:
  • a) Desalkylierung von erhaltenen Verbindungen der allgemeinen Formel I, worin R¹ eine Alkyl-, Alkenyl-, Cycloalkylmethyl- oder Phenalkylgruppe bedeutet, zu Verbindungen der allgemeinen Formel I, worin R¹ ein Wasserstoffatom darstellt;
  • b) Desacylierung von erhaltenen Verbindungen der allgemeinen Formel I, worin R¹ eine R^5-CO-Gruppe darstellt, zu Verbindungen der allgemeinen Formel I, worin R ein Wasserstoffatom darstellt;
  • c) Alkylierung von erhaltenen Verbindungen der allgemeinen Formel I, worin R ein Wasserstoffatom bedeutet, zu Verbindungen der allgemeinen Formel I, worin R¹ eine Alkyl-, Alkenyl-, Cycloalkylmethyl- oder Phenalkylgruppe bedeutet;
  • d) Reduktion von erhaltenen Verbindungen der allgemeinen Formel I, worin R¹ eine R^5-CO-Gruppe darstellt, zu Verbindungen der allgemeinen Formel I, worin R¹ eine Alkyl-, Alkenyl-, Cycloalkylmethyl- oder Phenalkylgruppe bedeutet;
  • e) Reduktion von erhaltenen Verbindungen der allgemeinen Formel I, worin R² eine Nitrogruppe darstellt, zu Verbindungen der allgemeinen Formel I, worin R² eine Aminogruppe darstellt, und gegebenenfalls anschließende Acylierung;
  • f) Reduktion von erhaltenen Verbindungen der allgemeinen Formel I, worin R² eine Aminogruppe darstellt, zu Verbindungen der allgemeinen Formel I, worin R² ein Wasserstoffatom darstellt;
  • g) Umwandlung der erhaltenen Base in ein Säureadditionssalz oder eines erhaltenen Säureadditionssalzes in die Base;
  • h) Umwandlung der erhaltenen Base oder eines Säureadditionssalzes in das N-Oxid.

and their N-oxides and their acid addition salts, is characterized in that a 4-hydroxypiperidine of the general formula II

wherein R has the meaning given above and

• R ^{4 is} an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part, a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or an R ⁵ CO group and
• R ^{5 represents} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 4 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a phenyl group or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part, or a salt thereof with 4 Reacting nitrofluorobenzene in an aprotic solvent in the presence of a strong base and, if appropriate, then subsequently subjecting the reaction product obtained to one or more of the following process steps:
  • a) dealkylation of compounds of the general formula I obtained, in which R ^{1 is} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group, to give compounds of the general formula I in which R ^{1 represents} a hydrogen atom;
  • b) deacylation of compounds of the general formula I, in which R ^{1 represents} an R ⁵ CO group, to give compounds of the general formula I, in which R represents a hydrogen atom;
  • c) alkylation of compounds of general formula I, in which R represents a hydrogen atom, to give compounds of general formula I, in which R ^{1 represents} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group;
  • d) reduction of compounds of general formula I obtained, in which R ^{1 represents} an R ⁵ CO group, to compounds of general formula I, in which R ^{1 represents} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group;
  • e) reduction of compounds of general formula I, in which R ^{2 represents} a nitro group, to compounds of general formula I, in which R ^{2 represents} an amino group, and optionally subsequent acylation;
  • f) reduction of compounds of the general formula I obtained, in which R ^{2 represents} an amino group, to compounds of the general formula I, wherein R ^{2 represents} a hydrogen atom;
  • g) converting the base obtained into an acid addition salt or an obtained acid addition salt into the base;
  • h) conversion of the base or an acid addition salt obtained into the N-oxide.

The reaction of piperidinol II with 4-nitrofluorobenzene is carried out in aprotic solvents such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, preferably in dimethylformamide. Examples of strong bases which may be mentioned are sodium hydride, potassium tert-butoxide, potassium tert-amylate, n-butyllithium, naphthalene sodium, preferably sodium hydride. The piperidinol II is intermediately converted into the corresponding alcoholate at temperatures between 0 and 80 ^° C., preferably at room temperature. By subsequent Addition of 4-nitrofluorobenzene at temperatures between 0 and 100 ⁰ , preferred. 50 to 60 ⁰ C is performed, the etherification of II to 4- (4-nitro-phenoxy) -piperidine I.

The subsequent process steps are carried out according to methods known per se.

The dealkylation, where alkyl also includes the meaning of alkenyl, cycloalkylmethyl and phenylalkyl, in particular benzyl, is carried out, for example, with chloroformic esters, such as ethyl chloroformate, β-chloroformate, β, β-trichloroethyl ester, without or in the presence of inert solvents, such as benzene, toluene, chloroform , at elevated temperature, preferably at the boiling point of the solvent. The intermediate product obtained is mixed with aqueous or alcoholic solutions of bases, such as sodium hydroxide solution / ethanol, potassium hydroxide solution / butanol, at elevated temperature, preferably the boiling point of the solvent, to give the corresponding desalkyl-4-phenoxypiperidine, ie for the compound of the general formula I, in the R ^{1 represents} a hydrogen atom.

The dealkylation in the special form of debenzylation, ie when using the compounds of general formula I obtained in which R ^{1 is} benzyl, is alternatively carried out by hydrogenolysis in the presence of catalysts, preferably palladium on carbon, in solvents such as methanol, ethanol, benzene, Cyclohexane, at 0 to 50 °, preferably room temperature, and a hydrogen pressure of 1 - 300 atmospheres, preferably 1 to 5 atmospheres.

The deacylation of compounds of the general formula I obtained, in which R ¹ denotes an R ⁵ CO group, is carried out, for example, with aqueous or alcoholic solutions of bases, such as sodium hydroxide solution / ethanol, potassium hydroxide solution / butanol, at elevated temperature, preferably the boiling point of the solvent , to the corresponding desacyl-4-phenoxypiperidine, ie to the compound of the general formula I in which R ¹ denotes a hydrogen atom.

The alkylation, where alkyl also includes the meaning of alkenyl, phenalkyl and cycloalkylmethyl, is carried out, for example, with alkylating agents _R ^4_ X, in which R ^{4 has} the meaning given above and X is a leaving group, such as alkyl halides, alkyl sulfonates, for example tosylates, alkyl sulfates inert solvents, such as acetone, methyl ethyl ketone, alcohols, such as methanol, ethanol, isopropanol, dimethylformamide etc. or without a solvent, using an auxiliary base, such as sodium carbonate, potassium carbonate, triethylamine, at temperatures of about 20 to 100 ° C. The alkylation can also be carried out by reacting compounds of the general formula I in which R is a hydrogen atom with acyl derivatives R -CO-X in which R ⁵ and X have the meaning given above, and subsequent reduction. Suitable acyl derivatives are, for example, acetyl chloride, propionyl chloride, butyryl chloride, pivaloyl chloride, cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, benzoyl chloride, phenylacetyl chloride.

The reduction of compounds of the general formula I obtained, in which R ^{1 represents} an R ⁵ CO group and R ^{5 has} the meaning given above, is carried out, for example, by reaction with a complex metal hydride as reducing agent in an anhydrous organic solvent and hydrolytic workup. Suitable reducing agents include lithium aluminum hydride (lithium hydride aluminate) and sodium dihydro-bis (2-methoxyethoxy) aluminate. Inert anhydrous ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethylene glycol diethyl ether are suitable as solvents, as are aromatic hydrocarbons such as benzene and toluene, or mixtures of the compounds mentioned. The temperature of the reaction can vary within wide limits, for example from 0 to 100 ° C. Usually, it is most convenient to carry out the reaction at the reflux temperature of the reaction mixture. At the preferred reflux temperature, the reaction is usually complete in 3 to 4 hours. The reactants can be used in equivalent amounts, but an excess of the reducing agent is preferred. Following the reaction with the reducing agent, the reaction product is obtained by treating the reaction mixture with an aqueous medium, such as water, dilute aqueous inorganic acids or bases or the like ren water-containing media, worked up. The product can be isolated by adjusting the pH as free base or as acid addition salts.

The reduction of compounds of the general formula I obtained, in which R ^{2 represents} a nitro group, to those in which R represents an amino group is carried out, for example, by reaction with hydrogen in the presence of metal catalysts, such as Raney nickel, palladium, platinum, platinum or palladium on carbon, in suitable solvents, e.g. alkanols, under pressures from 1 to 200 atm, preferably at atmospheric pressure, or by reduction with hydrazine in the presence of Raney nickel in alkanols, e.g. ethanol (see also Houben-Weyl, volume 11/1 , Page 360 ff.). Any subsequent acylation of the amino group is carried out by reaction with corresponding acid anhydrides or halides (cf., inter alia, Houben-Weyl, Vol. 8, p.655).

The reduction of the compounds of general formula I obtained, in which R represents an amino group, to those in which R represents a hydrogen atom takes place by diazotizing the amino group to the diazonium group (cf. Houben-Weyl, volume 10/3, pp. 1 ff .) and their subsequent reduction, e.g. with zinc, preferably hypophosphorous acid (cf. Houben-Weyl Volume 10/3, p. 115 ff.).

The salts obtained, e.g. the hydrochlorides can be converted into the free base by reaction with aqueous sodium or potassium hydroxide, which is then obtained by solvent extraction with a suitable, water-immiscible solvent, such as chloroform, dichloromethane, diethyl ether, benzene, toluene, cyclohexane etc. becomes. The free bases can also be obtained by reacting an acid addition salt with sodium methylate in methanol and isolating the base. Salts can also be converted into the base and further reacted with an acid into other salts, e.g. pharmacologically acceptable acid addition salts are transferred.

Acid addition salts are obtained by dissolving the 4-phenoxypiperidines in a suitable solvent, e.g. Water, acetone, a low molecular weight aliphatic alcohol (ethanol, isopropanoT) or ether (tetrahydrofuran, diethyl ether), which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtration, precipitation with a non-solvent for the acid addition salts or by evaporation of the solvent.

N-oxidation, i.e. the conversion of the bases of general formula I or their acid addition salts obtained into the N-oxides is preferably carried out with m-chloroperbenzoic acid or equivalent oxidizing agents, such as monopersulfuric acid, monoperphthalic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, at temperatures between 0 ° and 80 ° C. , expediently at room temperature. The usual inert solvents, e.g. Benzene, toluene, chloroform, methylene chloride or mixtures thereof are used.

The starting compounds of the general formula II are known or are prepared by known processes. Corresponding starting compounds II ^* and II ^** are used to prepare the compounds I ^* and I ^** .

The following examples serve to illustrate the invention without restricting it. "Schmp." means "melting point". Temperatures are given in ° C.

Examples example 1 1-methyl-4- (4-nitrophenoxy) -4-phenylpiperidine

A solution of 54 g of 1-methyl-4-phenyl-piperidine-4 is added dropwise to a suspension of 12.6 g of sodium hydride (80% in oil) in 200 ml of absolute dimethylformamide while stirring and excluding moisture at a temperature of 45 ° C. -ol in 200 ml of absolute dimethylformamide. Here, hydrogen evolution occurs. When the addition is complete, the mixture is stirred for a further 2 hours at 50 ° C., allowed to cool to room temperature and then a solution of 49.4 g of 4-fluoronitrobenzene in 100 ml of absolute dimethylformamide is added dropwise. The mixture is stirred for a further 2 hours and then poured into 800 ml of ice water. The precipitate that forms is filtered off and washed with water. Recrystallization from 250 ml of ethanol gives 52 g of the title compound, mp. 135-137 ° C.

Example 2 a) 4-Benzyl-1-methyl-4- (4-nitrophenoxy) piperidine

A solution of 40.0 g of 4-benzyl-1-methyl-piperidin-4-ol in 120 ml is added dropwise to a suspension of 8.76 g of sodium hydride (80% in Ul) in 200 ml of absolute dimethylformamide with stirring and with the exclusion of moisture absolute dimethylformamide. Here, hydrogen evolution occurs. When the addition is complete, the mixture is stirred at room temperature for 2 hours, 31.6 g of 4-fluoronitrobenzene are added dropwise and the mixture is stirred at 50 ° C. for 2 hours. The brown reaction mixture is then poured into 350 ml of ice water, stirred for 30 minutes and the precipitate which has separated out is filtered off and washed with water and petroleum ether. The crude product is dissolved in 150 ml of boiling ethanol, decanted from undissolved material, treated with activated carbon and filtered. 100 ml of petroleum ether are slowly added to the cooled filtrate, the precipitate formed is filtered off and washed with petroleum ether. You get through successive Concentrate the filtrate 38.9 g of the cream-colored title compound, mp. 116-117 ° C.

• b) 1-tert.-Butyl-4-(4-nitrophenoxy)-4-phenylpiperidin aus 1-tert.-Butyl-4-phenyl-piperidin-4-ol und 4-Fluornitrobenzol, Schmp. 153-154°C.
• c) 1-Isopropyl-4-(4-nitrophenoxy)-4-phenylpiperidin aus 1-Isopropyl-4-phenylpiperidin-4-ol und 4-Fluornitrobenzol.

You get analog

• b) 1-tert-butyl-4- (4-nitrophenoxy) -4-phenylpiperidine from 1-tert-butyl-4-phenyl-piperidin-4-ol and 4-fluoronitrobenzene, mp. 153-154 ° C.
• c) 1-Isopropyl-4- (4-nitrophenoxy) -4-phenylpiperidine from 1-isopropyl-4-phenylpiperidin-4-ol and 4-fluoronitrobenzene.

Example 3 a) 4- (4-Aminophenoxy) -1-methyl-4-phenylpiperidine

51 g of 1-methyl-4- (4-nitrophenoxy) -4-phenylpiperidine are dissolved in 1.5 liters of ethanol and hydrogenated at a hydrogen pressure of 1 atmosphere in the presence of platinum. The catalyst is filtered off, the mixture is concentrated to 300 ml and the deposited crystals are collected. Successive concentration of the filtrate gives 34.3 g of the title compound, mp. 173-174 ° C.

Analogously, one obtains by hydrogenation of the starting compounds mentioned

b) 4- (4-aminophenoxy) -1-tert-butyl-4-phenylpiperidine from 1-tert-butyl-4- (4-nitrophenoxy) -4-phenylpiperidine c) 4- (4-aminophenoxy) -4-benzyl-1-methylpiperidine [mp. 118-119 ⁰ C (Essigester / petroleum ether)] from 4-benzyl-1-methyl-4- (4-nitrophenoxy) piperidine d) 4- (4-aminophenoxy) -4-pheny1-1- (2-phenylethyl) piperidine from 4- (4-nitrophenoxy) -4-phenyl-1- (2-phenylethyl) piperidine Example 4 a) 1-Methy1-4-phenoxy-4-phenylpiperidine

A solution of 3.0 g of sodium nitrite is added dropwise at -10 ° C. to a solution of 10.0 g of 4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine in 12 ml of concentrated hydrochloric acid and 30 ml of water 18 ml water. The mixture is stirred for 45 minutes at -5 ° C., 50 ml of 50% hypophosphorous acid are added dropwise at -5 ° C. and the reaction mixture is left to stand at 0 ° C. for 24 hours. With ice cooling, the mixture is made alkaline with 6N sodium hydroxide solution and extracted with diethyl ether. After treating the organic phase with active carbon is dried over sodium sulfate and concentrated _- concentrated. After recrystallization from 100 ml of n-hexane, the residue gives 5.5 g of the title compound, mp. 99-101 ° C.

You get analog

b) 4-Benzyl-1-methyl-4-phenoxypiperidine [as hydrochloride of mp. 197-198 ° C (from ethanol)] from 4- (4-aminophenoxy) -4-benzyl-1-methylpiperidine. Example 5 a) 4-phenoxy-4-phenylpiperidine

9.0 g of 1-methyl-4-phenoxy-4-phenylpiperidine are added in portions to 100 ml of ethyl chloroformate at 80 ° C .; strong foaming is observed here. When the addition is complete, the mixture is boiled under reflux for 3 hours, the excess ethyl chloroformate is distilled off in vacuo and 120 ml of water and 15 ml of concentrated ammonia are added to the solid residue. The mixture is stirred well, the precipitate is filtered off and washed with water. The 1-ethoxycarbonyl-4-phenoxy-4-phenylpiperidine thus obtained (mp. 117-118 ° C. from ethanol) is refluxed for 4 hours with a solution of 15 g of potassium hydroxide in 150 ml of n-butanol; after cooling, the solution is mixed with 300 ml of water and extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate and concentrated. The title compound remains as a brownish oil. The hydrochloride melts at 192 ⁰ C (from ethanol).

You get analog

b) 4- (4-nitrophenoxy) -4-phenylpiperidine (oil) from 1-methyl-4- (4-nitrophenoxy) -4-phenylpiperidine over 1-ethoxycarbonyl-4- (4-nitrophenoxy) -4-phenylpiperidine (mp . 137-138 ° C). Example 6 a) 1-Isopropyl-4- (4-nitrophenoxy) -4-phenylpiperidine

6.0 g of 4- (4-nitrophenoxy) -4-phenylpiperidine, 2.8 g of potassium carbonate and 3.0 g of isopropyl bromide are refluxed in 50 ml of ethyl methyl ketone for 24 hours. The solvent is evaporated off, the residue is taken up in 100 ml of water and extracted with 100 ml of diethyl ether. The organic phase is dried over sodium sulfate, filtered through activated carbon and concentrated. 5.2 g of the title compound remain as a viscous, light yellow oil.

You get analog

b) 1-Allyl-4- (4-nitrophenoxy) -4-phenylpiperidine from 4- (4-nitrophenoxy) -4-phenylpiperidine and allyl bromide c) 4- (4-nitrophenoxy) -4-phenyl-1- (2-phenylethyl) piperidine from 4- (4-nitrophenoxy) -4-phenylpiperidine and 2-phenylethyl bromide. Example 7

• 1. Zu einer Lösung von 5,06 g'4-Phenoxy-4-phenylpiperidin und 2,5 g Triethylamin in 50 ml Dichlormethan tropft man bei 0-8°C 2,1 g Cyclopropancarbonsäurechlorid in 5 ml Methylenchlorid. Man rührt 2 Stunden bei 0°C, versetzt mit Wasser, trennt die organische Phase ab, extrahiert nochmals mit Dichlormethan, wäscht die vereinigten organischen Phasen mit verdünnter Salzsäure und Sodalösung, trocknet sie über Natriumsulfat und engt sie ein. Der ölige Rückstand (1-Cyclopropylcarbonyl-4-phenoxy-4-phenylpiperidin) wird in 50 ml Tetrahydrofuran gelöst, vorsichtig portionsweise mit 0,75 g Lithiumaluminiumhydrid versetzt und anschließend 1 Stunde unter Rückfluß gekocht. Nach dem Abkühlen wird zunächst tropfenweise 50 ml Wasser zugegeben und 2 mal mit je 50 ml Diethylether extrahiert. Nach dem Trocknen der vereinigten organischen Phasen wird das Lösungsmittel abdestilliert. Zurück bleiben 4,6 g der Titelverbindung als hellgelbes zähes öl.
• 2. Alternativ erhält man die Titelverbindung durch Alkylierung von 4-Phenoxy-4-phenylpiperidin mit Cyclopropylmethylbromid analog Beispiel 6 a).

a) 1-Cyclopropylmethyl-4-phenoxy-4-phenylpiperidine

• 1. To a solution of 5.06 g'4-phenoxy-4-phenylpiperidine and 2.5 g triethylamine in 50 ml dichloromethane is added dropwise at 0-8 ° C 2.1 g cyclopropanecarboxylic acid chloride in 5 ml methylene chloride. The mixture is stirred at 0 ° C. for 2 hours, water is added, the organic phase is separated off, extracted again with dichloromethane, the combined organic phases are washed with dilute hydrochloric acid and sodium carbonate solution, dried over sodium sulfate and concentrated. The oily residue (1-cyclopropylcarbonyl-4-phenoxy-4-phenylpiperidine) is dissolved in 50 ml of tetrahydrofuran, 0.75 g of lithium aluminum hydride is carefully added in portions and then boiled under reflux for 1 hour. After cooling, 50 ml of water are first added dropwise and the mixture is extracted twice with 50 ml of diethyl ether each time. After the combined organic phases have dried, the solvent is distilled off. This leaves 4.6 g of the title compound as a light yellow, viscous oil.
• 2. Alternatively, the title compound is obtained by alkylation of 4-phenoxy-4-phenylpiperidine with cyclopropylmethyl bromide analogously to Example 6 a).

You get analog

• 1. aus 4-Phenoxy-4-phenylpiperidin und Pivaloylchlorid und anschließende Reduktion des Zwischenproduktes 4-Phenoxy-4-phenyl-1-pivaloyl- piperidin mit Lithiumaluminiumhydrid oder alternativ
• 2. aus 4-Phenoxy-4-phenylpiperidin und Neopentylbromid analog Beispiel 6 a).

b) 1- (2,2-Dimethyl-1-propyl) -4-phenoxy-4-phenylpiperidine

• 1. from 4-phenoxy-4-phenylpiperidine and pivaloyl chloride and subsequent reduction of the intermediate 4-phenoxy-4-phenyl-1-pivaloyl-piperidine with lithium aluminum hydride or alternatively
• 2. from 4-phenoxy-4-phenylpiperidine and neopentyl bromide analogously to Example 6 a).

Example 8 a) 4- (4-Acetaminophenoxy) -1-methyl-4-phenylpiperidine

A solution of 0.85 g of acetyl chloride in 5 ml of benzene is added dropwise to a solution of 2.8 g of 4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine and 1.1 g of triethylamine in 10 ml of benzene. After stirring for 6 hours at room temperature, the mixture is concentrated, taken up with 30 ml of water and diethyl ether, shaken well, the organic phase is separated off, dried over sodium sulfate and concentrated. This leaves 2.8 g of the title compound as a tough yellow ul, which crystallizes from diethyl ether after standing for a long time, mp. 143-144 ° C.

You get analog b) 1-Methyl-4-phenyl-4- (4-pivaloylaminophenoxy) piperidine from 4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine and pivaloyl chloride. Example 9 1-methyl-4-phenoxy-4-phenylpiperidine N-oxide

1.5 g of 1-methyl-4-phenoxy-4-phenylpiperidine are dissolved in 4 ml of methanol and 1.7 g of 80% m-chloroperoxybenzoic acid, dissolved in methanol, are slowly added while cooling with ice. After stirring for 3 hours at room temperature, the solvent is stripped off and the residue is partitioned between concentrated sodium hydroxide solution and chloroform. The crude N-oxide hydrate remaining after drying of the chloroform phase and evaporation of the solvent is taken up in a little methanol and the equivalent amount of methanolic fumaric acid is added. 1 g of a colorless precipitate is obtained.

The use of ethereal hydrochloric acid instead of methanolic fumaric acid gives the hydrochloride.

Example 10 Tablets

4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine (10 kg), milk sugar (75 kg), corn starch (80 kg), finely divided silica (3 kg) and sodium lauryl sulfate (4 kg) are sieved and mixed. Polyvinylpyrrolidone (average M.G. 25,000; 5 kg) is dissolved in 20 l of water and the powder mixture is well moistened with this solution. The moist mixture is granulated through a sieve with a mesh size of 1.2 mm. After the granules have dried, sodium carboxymethyl cellulose (16 kg), talc (5 kg) and magnesium stearate (2 kg) are added. The finished mixture is pressed into tablets with a diameter of 8 mm and a weight of 200 mg.

Instead of 4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine, another compound according to the invention, e.g. 1-methyl-4-phenoxy-4-phenylpiperidine or the compounds in the form of a salt or N-oxide can be used.

Example 11 Capsules

4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine (10 kg) and milk sugar (spray dried, 210 kg) are mixed and filled into capsules of size 3.

Example 12 Ampoules

1-Methyl-4-phenoxy-4-phenylpiperidine hydrochloride (2,500 kg) and mannitol (4,000 kg) are dissolved in 80 liters of double-distilled water and made up to 100 liters with double-distilled water. The solution is filtered through a membrane filter with a pore diameter of 0.1μ, filled into 2 ml ampoules and sterilized at 100 ° C. for 1 hour.

pharmacology

The pronounced antiptotic and analgesic properties of the compounds according to the invention can be demonstrated in several model tests, the 4-phenoxypiperidines proving to be superior to the commercial antidepressant imipramine due to their stronger action, the longer duration of action and the analgesic component.

The comparison of the antiptotic and analgesic properties of the compounds according to the invention and that of imipramine was carried out using the example of the compounds listed in Table I.

Table I

• 1. Imipramine
• 2. 1-methyl-4-phenoxy-4-phenylpiperidine
• 3. 1-methyl-4- (4-nitrophenoxy) -4-phenylpiperidine
• 4. 4- (4-aminophenoxy) -4-benzyl-1-methylpiperidine
• 5. 4- (4-aminophenoxy) -1-methyl-4-phenylpiperidine
• 6. 4-Benzyl-1-methyl-4- (4-nitrophenoxy) piperidine
• 7. 4-Benzyl-1-methyl-4-phenoxypiperidine
• 8. 4-phenoxy-4-phenylpiperidine
• 9. 1-tert-butyl-4- (4-nitrophenoxy) -4-phenylpiperidine
• 10. 4- (4-acetaminophenoxy) -1-methyl-4-phenylpiperidine

Table II shows the DL ₅₀ values determined after oral administration and the ED ₅₀ values obtained in the various tests after oral administration (each mg / kg).

The pharmacological properties are determined using the following methods:

All experiments are carried out on female albino mice NMRI, 20-30 g body weight. 5 to 20 animals / dose are used and dose-response relationships are determined.

Antiptotic effects (reserpine antagonism)

Subcutaneous application of 2 mg / kg reserpine triggers ptosis in albino mice over a period of several hours [Reserpine-Ptosis, Domenjoz and Theobald (1959), Arch.Int.Pharmacodyn. 120.450]. The animals receive the test substances in various doses orally, 3 hours before the administration of reserpine. In the 2nd 3rd and 4th hour after reserpin application (ie 5, 6 and 7 hours after substance application) the degree of ptosis is determined according to a 3 - 2- 1 - 0 point system (full, moderate, mild, no ptosis). The tested substances antagonize the ptosis depending on the dose. The ED _{50 of} the antagonistic effect is evaluated in comparison to the daily reserpine control.

analgesia

• a) Focal beam test: Albino mice are placed with a focused heat beam, a thermal pain at the base of the tail and the time until the tail is pulled away is stopped. Usually it is in the range of 4 to 5 seconds. The tested substances cause a delayed reaction to the heat pain, i.e. a decreased heat pain reaction. The dose that increases the reaction time by 50% is determined. Literature: D'Amour, F.E. and Smith D.L. (1941) J.Pharmacol.Exp.Ther. 72, 74.
• b) Writhing test (acetic acid writhing): Intraperitoneal injection of 0.2 ml / 20 g mouse of a 0.75% acetic acid solution induces a typical syndrome running over the body with dorsiflexion, called "writhing" in albino mice. These "writhings" occurring in the course of the first half an hour pa are counted in the period from 5 to 20 minutes after administration of the acetic acid. The substances tested (administered 30 minutes before the injection of acetic acid) reduce the number of writhings. The dose is determined their number, based on the daily check, reduced by 50%. Literature: Koster, Anderson, de Beer (1959) Fed.Proc. 18, 412.
• c) Naloxone application (2 mg / kg sc.) 25 minutes after administration of the test substances is able to antagonize analgesic effects. The symbols +, (+), 0 in the table, column N, mean total, moderate or no naloxone antagonism.

Determination of lethal effects

The mice received food (Altromin ^R ) and water ad libitum. The substances to be tested were administered orally as solutions of various concentrations with the gavage in a volume of 10-20 ml / kg; 5 animals per dose were kept in Type II Makrolon cages. The observation period was 7 days. The DL ₅₀ , the dose at which 50% of the animals died, was determined graphically from the dose-response curve. Literature: Litchfield and Wilkoxon (1946) J.Pharm.Exp.Therap. 96/2, 99.

Claims (20)

Claims (DT, FR, IT, NL, BE, CH, GB, SE, LU) 1. 4-phenoxypiperidines of the general formula I

wherein R ^{1 is} a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, R ^{2 represents} a hydrogen atom, a nitro group, an amino group or an acylamino group and R ^{3 represents} a phenyl group or a benzyl group, as well as their N-oxides and their acid addition salts. 2. 4-phenoxypiperidines according to claim 1, characterized by the general formula I ^*

wherein _R ^{1 * represents} a hydrogen atom, a straight-chain alkyl group with 1 to 3 carbon atoms or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part, R ^{2 * represents} a hydrogen atom, a nitro group, an amino group or an alkylcarbonylamino group with 1 to 5 carbon atoms and R ^{3 * represents} a phenyl group or a benzyl group, as well as their N-oxides and their acid addition salts. 3. 4-phenoxypiperidines according to claim 2, in which R ^{1 * represents} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * represents} a hydrogen atom, a nitro group or an amino group and R ^{3 * represents} a phenyl group or a benzyl group, and their N-oxides and their acid addition salts. 4. 4-phenoxypiperidines according to claim 2, in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * is} a hydrogen atom, a nitro group or an amino group and R ^{3 * is} a phenyl group, and their pharmacologically acceptable acid addition salts. 5. 4-phenoxypiperidines according to claim 2, in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R is an amino group and R ^{3 * is} a phenyl group, and their pharmacologically acceptable acid addition salts. 6. 4-phenoxypiperidine according to claim 2, in which R ^{1 * is} a methyl group, R ^{2 * is} an amino group and R ^{3 * is} a phenyl group, and its pharmacologically acceptable acid addition salts. 7. 4-phenoxypiperidines according to claim 1, characterized by the general formula I ^**

wherein R ^{1 ** is} a branched-chain alkyl group with 3 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms or a cycloalkylmethyl group with 3 to 5 carbon atoms in the cycloalkyl part, R ^{2 ** represents} a hydrogen atom, a nitro group, an amino group or an alkylcarbonylamino group having 1 to 5 carbon atoms and 3 ^** R represents a phenyl group or a benzyl group, as well as their N-oxides and their acid addition salts. 8. 4-phenoxypiperidines according to claim 7, in which R ^{1 ** is} a branched-chain alkyl group having 3 to 5 carbon atoms, an allyl group 2 ^** or a cyclopropylmethyl group, R. represents a hydrogen atom, a nitro group or an amino group and R ^{3 ** represents} a phenyl group or a benzyl group, and also their N-oxides and their acid addition salts. 9. 4-phenoxypiperidines according to claim 7, in which R ^{1 ** is} an isopropyl group or tert-butyl group, R ^{2 ** is} a hydrogen atom, a nitro group or an amino group and R ^{3 ** is} a phenyl group, and their pharmacologically acceptable acid addition salts. 10. Medicament containing a pharmacologically acceptable compound according to claim 1 to 9. 11. Process for the preparation of the 4-phenoxypiperidines of the general formula I

wherein R is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cycloalkylmethyl group. 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, R ^{2 represents} a hydrogen atom, a nitro group, an amino group or an acylamino group and R ^{3 represents} a phenyl group or a benzyl group, and their N-oxides and their acid addition salts, characterized in that a 4-hydroxypiperidine of the general formula II

wherein R ^{3 has} the meaning given above and R ^{4 is} an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part, a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or an R ⁵ -CO group and R ^{5 represents} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 4 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a phenyl group or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part, or a Salt thereof is reacted with 4-nitrofluorobenzene in an aprotic solvent in the presence of a strong base and, if appropriate, the reaction product obtained is then subjected to one or more of the following process steps: a) dealkylation of compounds of the general formula I obtained, in which R ^{1 is} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group, to give compounds of the general formula I in which R ^{1 represents} a hydrogen atom; b) deacylation of compounds of the general formula I, in which R ^{1 represents} an R ⁵ CO group, to give compounds of the general formula I in which R ^{1 represents} a hydrogen atom; c) alkylation of compounds of the general formula I obtained, in which R1 represents a hydrogen atom, to compounds of the general formula I, in which R ^{1 represents} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group; d) reduction of compounds of the general formula I obtained, in which R ^{1 represents} an R ⁵ -CO group, to compounds of the general formula I, in which R ^{1 represents} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group; e) reduction of compounds of general formula I obtained, in which R ^{2 represents} a nitro group, to compounds of general formula I, in which R represents an amino group, and optionally subsequent acylation; f) reduction of compounds of the general formula I obtained, in which R ^{2 represents} an amino group, to compounds of the general formula I in which R ^{2 represents} a hydrogen atom; g) converting the base obtained into an acid addition salt or an obtained acid addition salt into the base; h) conversion of the base or an acid addition salt obtained into the N-oxide. Claims (AT) 1. Process for the preparation of 4-phenoxypiperidines of the general formula I

wherein R ^{1 is} a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, R ^{2 represents} a hydrogen atom, a nitro group, an amino group or an acylamino group and R ^{3 represents} a phenyl group or a benzyl group, and their N-oxides and their acid addition salts, characterized in that a 4-hydroxypiperidine of the general formula II

wherein R ^{3 has} the meaning given above and R is an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 7 carbon atoms in the cycloalkyl part, a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or an R ⁵ CO group and R ^{5 is} a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, one Cycloalkyl group having 3 to 7 carbon atoms, a phenyl group or a phenylalkyl group having 1 or 2 carbon atoms in the alkyl part, or reacting a salt thereof with 4-nitrofluorobenzene in an aprotic solvent in the presence of a strong base and optionally then the reaction product obtained one or more of the following Process steps subject: a) dealkylation of compounds of the general formula I obtained, in which R represents an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group, to give compounds of the general formula I in which R ^{1 represents} a hydrogen atom; b) deacylation of compounds of the general formula I, in which R ^{1 represents} an R ⁵ -CO group, to give compounds of the general formula I, in which R represents a hydrogen atom; c) alkylation of compounds of the general formula I obtained, in which R ^{1 is} a hydrogen atom, to give compounds of the general formula I in which R ^{1 is} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group; d) reduction of compounds of the general formula I obtained, in which R ^{1 represents} an R ⁵ -CO group, to compounds of the general formula I in which R ^{1 represents} an alkyl, alkenyl, cycloalkylmethyl or phenalkyl group; e) reduction of compounds of the general formula I obtained, in which R ^{2 represents} a nitro group, to compounds of general formula I, in which R ^{2 represents} an amino group, and optionally subsequent acylation; f) reduction of compounds of the general formula I obtained, in which R ^{2 represents} an amino group, to compounds of the general formula I in which R ^{2 represents} a hydrogen atom; g) converting the base obtained into an acid addition salt or an acid addition salt obtained into the base; h) conversion of the base or an acid addition salt obtained into the N-oxide. 2. The method according to claim 1, characterized in that 4-phenoxypiperidines of the general formula I ^*

wherein R ^{1 * represents} a hydrogen atom, a straight-chain alkyl group with 1 to 3 carbon atoms or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part, R ^{2 * represents} a hydrogen atom, a nitro group, an amino group or an alkylcarbonylamino group with 1 to 5 carbon atoms and R ^{3 * represents} a phenyl group or a benzyl group, and their N-oxides and their acid addition salts by reacting a 4-hydroxypiperidine of the general formula II ^* -

wherein R3 * has the meaning given above and R ^{4 * is} an alkyl group with 1 to 3 carbon atoms, a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part or an R ^{5 *} -CO group and R ^{5 * represents} a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, a phenyl group or a benzyl group, or a salt thereof with 4-nitrofluorobenzene in an aprotic solvent in the presence of a strong base and optionally subsequently the reaction product obtained one or more of the following Process steps subject: a) dealkylation of compounds of the general formula I ^{* obtained} , in which R1 represents an alkyl or phenalkyl group, to give compounds of the general formula I ^* in which R ^{1 * represents} a hydrogen atom; b) deacylation of compounds of the general formula I * obtained, in which R ^{1 * represents} an R ^{5 *} -CO group, to give compounds of the general formula-1 * in which R ^{1 * represents} a hydrogen atom; c) alkylation of compounds of the general formula I ^* in which R ^{1 *} denotes a hydrogen atom, to give compounds of the general formula I ^* in which R ^{1 *} denotes an alkyl or phenalkyl group; d) reduction of compounds of the general formula I ^{* obtained} , in which R ^{1 * represents} an R ^{5 *} -CO group, to compounds of the general formula I *, in which R ^{1 * represents} an alkyl or phenalkyl group, e) reduction of compounds of general formula I ^{* obtained} , in which R ^{2 * represents} a nitro group, to compounds of general formula I ^* , in which R ^{2 * represents} an amino group, and optionally subsequent acylation; f) reduction of compounds of the general formula I ^{* obtained} , in which R ^{2 * represents} an amino group, to compounds of the general formula I ^* , in which R ^{2 * represents} a hydrogen atom; g) converting the base obtained into an acid addition salt or an obtained acid addition salt into the base; h) conversion of the base or an acid addition salt obtained into the N-oxide. 3. The method according to claim 2, characterized in that 4-phenoxypiperidines of the formula I * in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * is} a hydrogen atom, a nitro group or an amino group and R ^{3 * is} a Phenyl group or a benzyl group, their N-oxides or their acid addition salts. 4. The method according to claim 2, characterized in that 4-phenoxypiperidines of the formula I ^* in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * is} a hydrogen atom, a nitro group or an amino group and R ^{3 * is} a Phenyl group mean, or their pharmacologically acceptable acid addition salts. 5. The method according to claim 2, characterized in that 4-phenoxypiperidines of the formula I ^* in which R ^{1 * is} a hydrogen atom, a methyl group or a benzyl group, R ^{2 * is} an amino group and R ^{3 * is} a phenyl group mean, or their pharmacologically acceptable acid addition salts. 6. The method according to claim 2, characterized in that the 4-phenoxypiperidine of the formula I ^* , wherein R1 * is a methyl group, R ^{2 * is} an amino group and R ^{3 * is} a phenyl group, or its pharmacologically acceptable acid addition salts. 7. The method according to claim 1, characterized in that 4-phenoxypiperidines of the general formula I ^**

wherein R ^{1 ** is} a branched-chain alkyl group with 3 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms or a cycloalkylmethyl group with 3 to 5 carbon atoms in the cycloalkyl part, R ^{2 ** represents} a hydrogen atom, a nitro group, an amino group or an alkylcarbonylamino group with 1 to 5 carbon atoms and R ^{3 ** is} a phenyl group or a benzyl group, and their N-oxides and their acid addition salts by reacting a 4-hydroxypiperidine of the general formula II ^**

wherein R ^{3 ** has} the meaning given above and R ^{4 ** is} a branched chain alkyl group with 3 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 3 to 5 carbon atoms in the cycloalkyl part or an R ^{5 **} -CO group and R ^{5 ** represents} an alkyl group with 2 to 4 carbon atoms, an alkenyl group with 2 to 4 carbon atoms or a cycloalkyl group with 3 to 5 carbon atoms, or a salt thereof with 4-nitrofluorobenzene in an aprotic solvent in the presence of a strong base and optionally subsequently the reaction product obtained is subjected to one or more of the following process steps: a) dealkylation of compounds of the general formula I ^{** obtained} , in which R ^{1 ** is} an alkyl, alkenyl or cycloalkylmethyl group, to give compounds of the general formula I ** in which R ^{1 ** represents} a hydrogen atom; b) deacylation of compounds of the general formula I ^** in which R ^{1 ** represents} an R ^{5 **} -CO group, to give compounds of the general formula I ** in which R ^{1 ** represents} a hydrogen atom; c) alkylation of compounds of the general formula I ^** in which R ^{1 ** is} a hydrogen atom, to give compounds of the general formula I ** in which R ^{1 ** is} an alkyl, alkenyl or cycloalkylmethyl group; d) Reduction of compounds of the general formula I ^{** obtained} , in which R ^{1 ** represents} an R ^{5 **} -CO group, to compounds of the general formula I ^** , in which R ^{1 **} alkyl, alkenyl or cycloalkylmethyl group means; e) reduction of compounds of the general formula I ^** , in which R ^{2 ** represents} a nitro group, to compounds of the general formula I ^** , in which R ^{2 ** represents} an amino group, and optionally subsequent acylation; f) Reduction of compounds of the general formula I ^{** obtained} , in which R ^{2 ** represents} an amino group, to compounds of the general formula I ^** , in which pure represents a hydrogen atom; g) converting the base obtained into an acid addition salt or an acid addition salt obtained into the base; h) conversion of the base or an acid addition salt obtained into the N-oxide. 8. The method according to claim 7, characterized in that 4-phenoxypiperidines of the general formula I ^** , in which R ^{1 ** is} a branched-chain alkyl group having 3 to 5 carbon atoms, an allyl group or a cyclopropylmethyl group, R ^{2 ** is} a hydrogen atom, represents a nitro group or an amino group and R ^{3 ** represents} a phenyl group or a benzyl group, produces their N-oxides or their acid addition salts. 9. The method according to claim 7, characterized in that 4-phenoxy-piperidines of the general formula I **, in which R .... is an isopropyl group or tert-butyl group, R ^{2 ** is} a hydrogen atom, a nitro -3 ^** group or an amino group and R .. is a phenyl group, or its pharmacologically acceptable acid addition salts.